Cancer is thought to arise from a series of somatic genome and epigenome defects that allow the cell to evade the rules that control the growth and organization of normal cells (1, 2). In order for genetic and epigenetic somatic genome alterations to drive cancer initiation and progression, the cancer cell would need to maintain those changes in a heritable way throughout disease progression for as long as such changes confer a selective advantage. Genetic alterations are maintained by semiconservative DNA replication and have been implicated in carcinogenesis and disease progression (3). However, epigenetic processes present a fundamental paradox in this regard: They are, by definition, potentially heritable across cell divisions and are stable over time (4, 5), but they can also be plastic (5, 6). For instance, recent reports have suggested that the epigenetic process of DNA methylation can be dynamic and reversible in both replication-dependent [for example, during differentiation and development (6)] and replication independent [for example, cyclical methylation patterns during transcription (7, 8)] processes. Additionally, DNA methylation marks can occur at both copies of a given locus or occur at only one copy, resulting in allele-specific methylation (ASM) (9-11). Unfortunately, most previous reports on DNA methylation in human cancers have only examined total methylation (TM) at an allele-agnostic level, and little is known about the maintenance of ASM in human neoplasia.
Consequently, it is currently unclear which DNA methylation and other epigenetic alterations can be maintained stably as driver genome alterations fueling cancer initiation and progression. A lack of such evidence has dampened enthusiasm for using DNA methylation alterations, which can be more frequent than genetic alterations (12), as targets for biomarker development and therapeutic intervention. Here, we show that, although there is marked heterogeneity in DNA methylation profiles in men with lethal metastatic prostate cancer, each individual's distinct DNA methylation signature is tightly maintained in disseminated metastases.